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United States Patent |
5,130,336
|
Davis
|
July 14, 1992
|
Method for treatment for neuro-muscular incontinence
Abstract
Treating a patient for neuro-muscular incontinence by administering a
thiol-S-(2-diethyl-aminoethyl)-ester compound selected from the group
consisting of trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester,
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester,
palmitoyl-thio-S-(2-diethylaminoethyl)-ester,
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester,
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester,
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester, and
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.
Inventors:
|
Davis; William M. (Tucson, AZ)
|
Assignee:
|
United Pharmaceuticals, Inc. (Tucson, AZ)
|
Appl. No.:
|
792799 |
Filed:
|
November 15, 1991 |
Current U.S. Class: |
514/513 |
Intern'l Class: |
A61K 031/21 |
Field of Search: |
514/513
|
References Cited
Attorney, Agent or Firm: Miller; Austin E.
Claims
I claim:
1. In a method of treating a patient for neuro-muscular incontinence, the
step which comprises administering to said patient a
thiol-S-(2-diethyl-aminoethyl)-ester compound selected from the group of
trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester,
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester,
palmitoyl-thio-S-(2-diethylaminoethyl)-ester,
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester,
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester,
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester, and
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.
2. The method defined in claim 1 wherein said ester is administered in a
dosage of about 15 mg/kg.
3. The method defined in claim 1 wherein said ester is administered as a
hydrochloride.
4. The method defined in claim 1 wherein said ester is further administered
in a dosage to enhance bladder capacity.
5. The method defined in claim 1 wherein said ester is further administered
in a dosage to provide moderate antidiuretic effect.
6. The method defined in claim 1 wherein said ester is further administered
in a dosage to re voiding frequency.
7. The method defined in claim 1 wherein said ester is further administered
in a dosage of 100-400 mg tablets.
8. The method defined in claim 1 wherein said ester is further administered
in microspheres.
9. The method defined in claim 1 wherein said ester is further administered
by intravenous injection.
10. The method defined in claim 1 wherein said ester compound is
trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl.
11. The method defined in claim 1 wherein said ester compound is
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl.
12. The method defined in claim 1 wherein said ester compound is
palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl.
13. The method defined in claim 1 wherein said ester compound is
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl.
14. The method defined in claim 1 wherein said ester compound is
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl.
15. The method defined in claim 1 wherein said ester compound is
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl.
16. The method defined in claim 1 wherein said ester compound is
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl.
Description
BACKGROUND OF THE INVENTION
The present invention relates to a method of treating patients for
neuro-muscular incontinence. More particularly, the invention relates to
the relief of incontinence created by smooth muscle spasm, and relates to
the use of new pharmaceutical compounds having useful antispasmodic
properties.
DESCRIPTION OF THE PRIOR ART
It is known to use antispasmodic drugs to relieve spasms of the smooth
muscles. As disclosed in my U.S. Pat. No. 4,857,535, granted Aug. 15,
1989, the purpose of an antispasmodic drug is to relieve spasms of the
smooth muscles. Such spasms may be due to exaggerated impulses from the
parasympathetic branch of the autonomic nervous system or the muscle may
be intrinsically stimulated into a spasm, most likely from chemical
changes in the surrounding tissue. Atropine may be used to treat spasms
due to exaggerated impulses from the parasympathetic branch of the
autonomic nervous system (neurotropic effect) while substances such as
papaverine have the ability to decrease intrinsically the contractility of
the smooth muscle, and has the ability to relax smooth muscles directly by
what is called a "musculotropic effect".
U.S. Pat. No. 2,390,555 discloses a class of compounds comprising
di-N-substituted aminoethyl esters of diphenylthioacetic acid of the
general formula (C.sub.6 H.sub.5).sub.2 --CH--COS--CH.sub.2 CH.sub.2 --R
in which R represents a disubstituted amino radical of either the
diethylamino group, the morpholino group or the piperidino group with N as
the point of attachment. This patent discloses that the thio analogs of
certain disubstituted acetic acid esters of aminoalcohols have desirable
antispasmodic properties. These compounds have proven to be very effective
and are widely used as antispasmodics without encountering the undesirable
side reactions due to excessive neurotropic effect.
U.S. Pat. No. 4,432,977 discloses new uses, especially for the dilation of
the smooth muscles of the upper urinary tract, of the compounds disclosed
in U.S. Pat. No. 2,390,555.
In Compte Rendu de la Societe de Biologie, 140, pp 477-b 9, (1946) Dupre,
Levy and Tchoubar disclose a series of compounds having the formula
C.sub.6 H.sub.5 (R)CH--C(O)--S--CH.sub.2 CH.sub.2 N(CH.sub.2
CH.sub.3).sub.2 where R is either a phenyl group, a propyl group, an
isopropyl group, a butyl group or an isoamyl group. These compounds are
all disclosed as being spasmolytic agents.
Compounds of the same general formula given above are disclosed by Tchoubar
and Letellier-Dupre in Bulletin de la Societe Chimique, pp 792-4 (1947)
wherein R was a phenyl group, an ethyl group, a propyl group, an isopropyl
group, a butyl group, an isoamyl group or hydrogen.
In Farmakol. i. Toksikol., pp 10-17 (1956), Liberman discloses a class of
compounds having the general formula (C.sub.6 H.sub.5).sub.2 CHCOSCH.sub.2
CH.sub.2 N--R.sub.2, wherein both R's are the same and are selected from
methyl, ethyl, propyl and butyl groups; and a class of compounds having
the general formula (C.sub.6 H.sub.5)--CH(C.sub.6 H.sub.11)COSCH.sub.2
CH.sub.2 N--R.sub.2, wherein both R's are the same and are selected from
methyl, ethyl, propyl and butyl groups.
C. A. Buehler et al in the Journal of Medicinal Chemistry, 6, pp 230-3
(1963) disclose physiologically active compounds of the general formula
RR'C(OH)COS(CH.sub.2).sub.x NR.sub.2 ".multidot.HCl wherein R and R' are
aryl groups, x is 2 or 3, and R.sub.2 " is a methyl or ethyl group.
R. O. Clinton et al in the Journal of the American Chemical Society, 68, pp
2076-7 (1946) disclose synthesis of a number of dialkyl aminoalkyl
diarylthiolacetates including fluorene-9-carbothioic acid,
S-[2-diethylaminoethyl]ester.
OBJECTS OF THE INVENTION
It is an object of this invention to provide a new method for treatment for
neuro-muscular incontinence, and having a highly useful and effective
influence upon the bladder.
Still another object is to provide a new method for enhancing bladder
capacity and reducing the voiding frequency.
Still another object of this invention is to provide a rapid and accurate
method to evaluate the pharmacologic action of a drug relevant to the
urinary tract, which avoids the use of anesthesia and of external infusion
into the bladder.
Still another important object of the present invention is to provide a
method of treatment for neuro-muscular incontinence by introducing a
highly effective agent which is free of undesirable side effects.
Other objects and advantages of this invention will further become apparent
hereinafter and in the drawings.
DRAWINGS
In the drawings which are submitted as illustrative but are not intended to
define or limit the scope of the invention,
FIG. 1 is a schematic diagram illustrating an experimental set up for the
measurement of volume evoked micturition reflex (VEMR). The inset shows
the principal parameters, wherein L means latency, C means capacity of
first micturition volume, and O means total urine produced per period of
observation.
FIG. 2 shows histograms of the distribution of VEMR parameters over a
24-hour period. The circadian rhythm of spontaneous voidings without
furosemide is also shown. The mean voided volume for the entire period is
also shown. Indicated values are mean .+-.SE.
FIG. 3 shows typical recording of VEMR showing the characteristic pattern
of voiding under different conditions.
SUMMARY OF THE INVENTION
These and other objects are met by administering to a patient suffering
from neuro-muscular incontinence a safe and effective amount of a
-thio-S-(2-diethylaminoethyl)-ester compound of a radical selected from
the group consisting of trimethylacetyl, 1-cyclohexyl-1-phenylacetyl,
palmitoyl, 4-t-butyl, phenylacetyl, 4-phenyl-butyryl and 2-ethyl-butyryl.
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester, for
example, has the following formula:
##STR1##
The others of the group have corresponding formulae simply substituting for
the 1-cyclohexyl-1-phenylacetyl group the individual moiety selected.
It has now been surprisingly discovered that each of these compounds has a
remarkably beneficial effect on the bladder and has positive effect for
the treatment of patients for neuro-muscular incontinence. The compound
can be administered orally, typically in tablets of 100-400 mg, or by
intravenous injection. It is also possible to encapsulate microspheres of
the compound in the form of a liquid suspension for administration to
patients.
It has further been discovered that the administration of the compound
produces larger bladder capacity, tends to produce a significant reduction
in the frequency of voidings and, when used in conjunction with furosemide
or other diuretic agent achieves a highly useful anti-diuretic effect, and
also provides a highly advantageous latency of voidings.
EXAMPLES
The Examples which follow are intended to be illustrative of the invention
but are not intended to define or to limit the scope of the invention
which is defined in the appended claims.
There is an acute clinical need for the development of drugs and
pharmacologic methods that can be used for the identification and rapid
evaluation of drugs useful in treating urinary incontinence. The most
common condition that can be treated pharmacologically is incontinence due
to detrusor instability (DI). Most available drugs increase bladder
capacity by suppressing the premature voiding contractions present in DI
patients. Such drugs also decrease the frequency of voluntary voiding that
is associated with urgency.
To test the efficacy of drugs on DI, pharmacologists use an array of in
vitro and in vivo methodologies that range from binding studies and
isometric responses to complex urodynamic investigations. The
pharmaceutical industry frequently is challenged with performing this
quantitative evaluation of a number of drugs that are analogs to each
other but possess sharply different specific properties for the treatment
of DI. This evaluation should consist of a simple set of parameters so
that comparisons can be made to analogs as well as agents currently in
clinical use.
In the following Examples, we have, in addition to reporting the results of
treatment for neuro-muscular incontinence with the use of the compounds of
the invention, tested and reported a multiplicity of comparative
compounds.
The screening method used avoids the use of anesthesia and of external
infusion into the bladder relying on the physiological stimulation of the
VEMR by diuresis.
Mature female Sprague-Dawley rats weighing 240-310 gm were placed in
restrainer cages (Braintree Scientific, Inc., Mass.) which afforded access
to food and water. Some limited lateral and back and forth movement was
allowed in the cages. Under the rear of the rat a collecting funnel and
weight measuring device was secured. The collector was secured to a
Statham UC3 strain transducer, the output of which was amplified by a
Gould bridge amplifier. Data collected were monitored on a Gould 2400
polygraph. For each VEMR, the weight of the volume voided, and the time of
voiding were recorded on the polygraph.
To evaluate the relative pharmacologic efficacy of each drug under study, 1
mg/kg furosemide along with the drug to be evaluated was diluted in 5 ml
of saline and injected subcutaneously.
In baseline studies the bladder capacity for each voiding varies in a
circadian manner. Consistent bladder capacities were obtained with the
addition of furosemide.
Rats received approximately equimolar concentrations (2.8.times.10.sup.-3
M) of analogs to the compounds of the invention. To establish a standard
of comparison, test drugs representing Ca.sup.++ blocking,
anticholingerics and a K.sup.+ channel opener were also examined.
This method (subcutaneous injection of a fluid and diuretic load
simultaneously with a pharmacologic agent) proved an accurate and
reproducible means of eliciting VEMR. This model allows rapid evaluation
of various drugs designed to increase bladder capacity and decrease the
frequency of voiding. It is particularly useful in evaluating the relative
efficacy of drugs that are chemical analogs.
This method is based on the evaluation of the voiding parameters provided
by the VEMR which has itself been extensively studied. (Durant et al 1988;
Durant and Yaksh 1988a, 1988b; Sosnowski and Yaksh 1990). The drugs
studied were compared with other drugs that are currently under
investigation. The advantage of this test these drugs is that it avoids
all surgical interventions, minimizes the number of animals used, and can
be used on a relatively large scale. It is also possible to make
comparisons using a single dose and thus test the efficacy of action in a
wide variety of drugs.
TEST METHOD
Baseline Studies
With this set-up, urine output, frequency, volume per micturition and
micturition time were monitored for any 24-hour period. Experiments were
then performed from 9:00 a.m. to the same the next day in order to
establish the circadian VEMR values. Baseline values of micturition
frequency, volume and output, initially measured over a 24-hour period,
showed a wide variation in volume voided and diuresis. The method was thus
modified to produce a more reliable diuretic load that is not dependent on
the circadian rhythm.
Controls
To evaluate the pharmacologic efficacies of the various drugs under study,
a single subcutaneous injection of a 5 ml saline fluid load with 1 mg/kg
furosemide was initially given to rats to establish the control values of
the parameters measured.
Study Animals
To obtain a controlled amount of diuresis and avoid circadian variations in
urine flow, 1 mg/kg furosemide and 5 ml of saline were added to each drug
under study. VEMR were observed for three hours as a rule, except in
instances were the latency was more than three hours. On such occasions
the period of recording is indicated specifically in the results. The
parameters of VEMR considered in this study are defined as follows:
V.sub.o : volume voided on first micturition
V: mean volume voided during entire study period
D: diuretic effect over entire study period
F: frequency of micturition
L: latency period from time of injection to first micturition.
In addition to the quantitative data obtained for the parameters given
above, the pattern of micturition was qualitatively identified,
particularly the incidence of dribbling.
Tests were done using (1) baseline--no drug, (2) control--furosemide, (3)
atropine (1 mg/kg), (4) oxybutinin (18 mg/kg), (5) terodiline (1.5 mg/kg),
(6) diltiazem (18 mg/kg), (7) lamakalim (0.016 mg/kg), (8) urecholine, and
the drugs listed:
COMPOUNDS ACCORDING TO THIS INVENTION
trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
COMPARATIVE COMPOUNDS
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
1-naphtylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
Statistical Methods
Data were compared using ANOVA (analysis of variance model) and values
given are expressed as .+-. standard error.
RESULTS
The results of measured parameters for controls with furosemide (1 mg/kg)
together with the listed drugs are shown in Tables 1-5.
TABLE 1
__________________________________________________________________________
Volume Voided on First Micturition (Vo)
Vo .+-. SE
% C
__________________________________________________________________________
Compounds According To This Invention
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
5.30
.57 83
1-cyclohexyl-l-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.07
.39 41
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.27
.61 48
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.37
.40 51
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.35
1.06
51
Phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.12
.32 42
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.43
.94 53
Comparative Compounds
Baseline (no drug) .cndot.
.cndot.
.cndot.
Control 2.89
.48 0
Atropine 1 mg/kg 2.83
.57 -2
Oxybutynin 2.76
.44 -4
Terodiline 1.5 mg/kg 3.57
.45 24
Diltiazem 3.30
.51 14
Lemakalim 0.16 mg/kg 4.37
.38 51
Urecholine 3.40
.73 18
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
3.85
.99 33
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
3.30
.57 14
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.82
.72 32
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.32
.35 15
Fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.55
.35 -12
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
1.77
.23 -39
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.95
.46 2
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.95
.77 2
__________________________________________________________________________
Key:
Vo = volume voided on first micturition
.+-. SE = standard of error
% C = percent change from control
TABLE 2
__________________________________________________________________________
Mean Volume (V) Voided During Entire Period of Study
V .+-. SE
% C
__________________________________________________________________________
Compounds According To This Invention
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
5.30
.57 71
1-cyclohexyl-l-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.07
.40 31
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.57
.53 47
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.32
.40 39
Phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.33
.36 40
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.53
1.03
46
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.12
.70 33
Comparative Compounds
Baseline (no drug) .cndot.
.cndot.
.cndot.
Control 3.10
.41 0
Atropine 1 mg/kg 3.16
.41 2
Oxybutynin 2.77
.41 -11
Terodiline 1.5 mg/kg 3.62
.44 17
Diltiazem 3.29
.51 6
Lemakalim 0.16 mg/kg 4.37
.40 41
Urecholine 2.84
.56 -8
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
4.09
.76 32
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
3.46
.63 12
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.98
.67 28
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.32
.35 7
Fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.55
.35 -18
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
2.45
.26 -21
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.90
.49 -6
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.97
.77 -4
__________________________________________________________________________
Key:
V = mean volume
.+-. SE = standard of error
% C = percent change from control
TABLE 3
__________________________________________________________________________
Diuretic Effect (D) Over Entire Study
D .+-. SE
% C
__________________________________________________________________________
Compounds According To This Invention
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
5.30
.47 -45
1-cyclohexyl-l-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.07
.39 -58
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
6.67
1.07
-31
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
4.93
.62 -49
Phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
6.85
1.45
-29
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
6.50
1.63
-33
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
7.13
.94 -26
Comparative Compounds
Baseline (no drug) .cndot.
.cndot.
.cndot.
Control 9.67
2.11
0
Atropine 1 mg/kg 4.78
.61 -51
Oxybutynin 4.20
.90 -57
Terodiline 1.5 mg/kg 4.12
.56 -57
Diltiazem 3.90
.80 -60
Lemakalim 0.16 mg/kg 4.37
.38 -55
Urecholine 10.72
2.53
11
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
8.00
1.16
-17
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
5.70
1.67
-41
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
6.00
.80 -38
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.32
.35 -66
Fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.55
3.50
-74
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
5.52
.41 -43
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
5.73
.72 -41
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
3.22
.71 -67
__________________________________________________________________________
Key:
D = diuretic effect
.+-. SE = standard of error
% C = percent change from control
TABLE 4
__________________________________________________________________________
Frequency of Micturition (F) Over Entire Recording Period
F .+-. SE
% C
__________________________________________________________________________
Compounds According To This Invention
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.00
0 -66
1-cyclohexyl-l-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.00
0 -66
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.50
.22 -49
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.17
.17 -60
Phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.50
.22 -49
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.50
.29 -49
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.83
.17 -37
Comparative Compounds
Baseline (no drug) .cndot.
.cndot.
.cndot.
Control 2.92
.38 0
Atropine 1 mg/kg 1.67
.33 -43
Oxybutynin 1.50
.19 -49
Terodiline 1.5 mg/kg 1.17
.17 -60
Diltiazem 1.17
.17 -60
Lemakalim 0.16 mg/kg 1.00
0 -66
Urecholine 3.67
.33 26
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
2.25
.63 -23
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
1.50
.22 -4
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.70
.33 -42
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.00
0 -66
Fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.00
0 -66
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
2.33
.21 -20
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
2.17
.31 -26
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
1.17
.17 -60
__________________________________________________________________________
Key:
F = frequency of micturition
.+-. SE = standard error
% C = percent change from control
TABLE 5
__________________________________________________________________________
Latency Period (Lo) From the Time of Injection
Lo .+-. SE
% C
__________________________________________________________________________
Compounds According To This Invention
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
36.8
4.4 57
1-cyclohexyl-l-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
132.2
25.2
463
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl
36.7
2.2 56
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
60.5
16.5
157
Phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
53.8
18.9
129
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
27.5
2.1 17
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
25.8
2.2 10
Comparative Compounds
Baseline (no drug) .cndot.
.cndot.
.cndot.
Control 23.5
8.8 0
Atropine 1 mg/kg 33.7
4.8 43
Oxybutynin 50.4
7.5 114
Terodiline 1.5 mg/kg 94.8
26.0
303
Diltiazem 157.5
21.9
570
Lemakalim 0.16 mg/kg 37.5
3.2 60
Urecholine 11.5
1.2 -51
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
31.2
3.2 33
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
73.5
24.9
213
phenoxyacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
25.3
1.9 8
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
106.0
41.6
351
Fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
130.5
43.0
455
t-butyl-acetyl-thiol-S-(2-diethylaminoethyl-ester.HCl
34.7
3.3 48
2-propyl-pentanoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
45.7
3.9 94
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl
85.5
40.7
264
__________________________________________________________________________
Key:
Lo = latency period
.+-. SE = standard of error
% C = percent change from control
TABLE 6
__________________________________________________________________________
TABLE 3
TABLE 1
TABLE 2 (1-11) TABLE 4 TABLE 5
COMPOSITE RANK
(1-7) (1-7) DIURETIC
(1-7) (1-10) TABLES
TABLES
1ST VOID
MEAN VOL.
VOL. FREQUENCY
LATENCY
1-4 1-5
__________________________________________________________________________
Part I
COMPOSITE RANKS OF COMPOUNDS ACCORDING TO THIS INVENTION
trimethylacetyl-thio-S-(2-
1 1 6 1 8 1 2
diethylaminoethyl)-ester.HCl
1-cyclohexyl-1-phenylacetyl-
3 3 8 1 2 3 1
thiol-S-(2-diethylaminoethyl)-
ester.HCl
palmitoyl-thio-S-(2-
2 2 4 3 8 2 4
diethylaminoethyl)-ester.HCl
4-t-butyl-benzoyl-thiol-S-(2-
2 2 6 2 6 3 3
diethylaminoethyl)-ester.HCl
phenylacetyl-thio-S-(2-
3 2 4 3 6 3 3
diethylaminoethyl)-ester.HCl
4-phenyl-butyryl-thio-S-(2-
2 2 4 3 9 2 5
diethylaminoethyl)-ester.HCl
2-ethyl-butyryl-thio-S-(2-
2 3 3 4 9 3 6
diethylaminoethyl)-ester.HCl
Part II
Composite Ranks of Comparative Compounds
2-phenyl-butyryl-thio-S-(2-
4 3 2 5 8 5 7
diethylaminoethyl)-ester.HCl
1-naphthylacetyl-thio-S-(2-
5 5 5 3 5 7 8
diethylaminoethyl)-ester.HCl
phenoxyacetyl-thiol-S-(2-
4 4 5 4 9 6 10
diethylaminoethyl)-ester.HCl
4-biphenyl-carboxyl-thiol-S-
5 5 10 1 3 9 9
(2-diethylaminoethyl)-ester.HCl
fluorene-carboxyl-thiol-S-(2-
6 6 11 1 2 12 10
diethylaminoethyl)-ester.HCl
t-butyl-acetyl-thiol-S-(2-
7 7 5 5 8 12 14
diethylaminoethyl-ester.HCl
2-propyl-pentanoyl-thiol-S-(2-
6 6 5 5 7 13 15
diethylaminoethyl)-ester.HCl
adamante-carboxyl-thiol-S-(2-
6 6 10 2 4 12 11
diethylaminoethyl)-ester.HCl
__________________________________________________________________________
Volume Voided on First Micturition
Table 1 lists the volume voided on first micturition (V.sub.o) by the study
animals after injection with the listed drug. In evaluating the
pharmacologic efficacy of these drugs in the treatment of UI an increase
in the volume voided on first micturition is important. A higher volume on
first micturition indicates the drug's effectiveness in allowing the
bladder to store fluid prior to micturition, thus eliminating the urgency
symptomatic of UI.
Clearly, trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl exhibits
exceptional performance in this effect, allowing a volume on first
micturition 83% higher than that exhibited by study animals in the control
group. Also providing excellent performance are
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl,
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl, and
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl, each inducing a
volume on first micturition at least 50% higher than that exhibited by the
control group.
Mean Volume Voided During Study Period
Table 2 lists the mean volume voided by the control animals during the
entire study period for each drug tested. Similar to the volume voided on
first micturition, a high mean volume voided during the period of study is
preferred. Again, trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl
exhibits outstanding performance in this regard, increasing the mean
volume by 71% over the control group.
The mean volume voided during the study period indicates not only the
effect of the drug in allowing the bladder to maintain fluid prior to
micturition, but is further indicative of the drug's long-term
effectiveness. High volume of first micturition is indicative of the
effect of the drug in allowing the bladder to maintain fluid. While
preferred, this effectiveness may be short-lived or compensated for by
high frequency of micturition.
Palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl,
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl and
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl all exhibit at least a
40% increase in the mean volume.
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl exhibits a 39%
increase.
Diuretic Effect
Table 3 measures the diuretic effect of the drugs over the entire study
period. A minimum diuretic effect is preferred. A drug exhibiting a high
diuretic effect will draw water from the body fluid tending to fill the
bladder with fluid at a faster rate than normal. This faster filling of
the bladder causes a greater frequency of micturition, a symptom of UI.
However, a drug which exhibits an anti-diuretic effect tends to prevent
the collection of fluid in the bladder. Although this may diminish
frequency, urgency (the tendency for a VEMR to occur prior to having a
full bladder) may not be alleviated by administration of the drug. Hence,
a drug which exhibits an anti-diuretic effect is generally not desirable
for the treatment of UI.
Compounds exhibiting low or moderate diuretic effect were
2-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl,
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl,
palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl and
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl.
TABLE 4
Table 4 measures the frequency of micturition over the entire recording
period. High frequency of micturition is the symptom most bothersome to
the patients suffering UI. Therefore, decrease in micturition frequency is
important.
However, changes in frequency upon administration of a drug cannot be
viewed in a vacuum. A decrease in frequency brought about by a drug
exhibiting anti-diuretic effect is not preferred for the reasons stated
above.
Trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl,
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl,
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl, and Urecholine all
exhibited a 66% decrease in frequency of micturition over the control
group. Adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl and
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl also proved
effective in reducing frequency, showing a reduction of 60% but the drugs
outside the scope of this invention were found lacking in other respects.
TABLE 5
Table 5 indicates the latency period, the period of time between ingestion
of a fluid volume and initial micturition. Preferably this time period
should be long, indicating the potential for low frequency of micturition.
However, of the two statistics, change in frequency is better indicative of
the drug's performance in the treatment of UI. Measurements of latency may
be inexact in clinical evaluation of the drugs, as patients may ingest
fluid volumes at various periods during which the drug is taking effect.
Moreover, like frequency data, latency measurements are susceptible to
variations induced by a drug's anti-diuretic effect.
Desirable latency periods were exhibited by
1-cyclohexyl-1-phenylacetyl-thiol-S-(2-diethylaminoethyl)- ester.HCl,
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl,
4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl,
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl and
1-naphthylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl.
CONCLUSIONS
In summary, five categories of drug activity were measured: frequency, mean
volume voided during the observation period, the diuretic effect of the
test drug, the volume at first voiding and the latency period between
ingestion of the volume load and first micturition. Ideally, a drug
utilized in the treatment of UI would exhibit all of the following:
greatly decreased frequency, increased mean volume, negligible
anti-diuretic effect, large volume upon first voiding and, possibly,
increased latency time.
Because these factors do not work independently of each other, certain
preferred reactions may be induced and offset by less favorable reactions
for other factors. For example, although low frequency an period are
preferred, these types of reactions may be artificially induced by a drug
which has a high anti-diuretic effect.
For example, 4-biphenyl-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl,
adamante-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl and
fluorene-carboxyl-thiol-S-(2-diethylaminoethyl)-ester.HCl all induce a
desirable reduction in frequency of micturition. However, these compounds
also induce very high anti-diuretic effects causing low volume urination.
Hence, these drugs would have minimum effect on the bladder wall
contractions caused by the entrance of small amounts of fluid into the
bladder. Moreover, the anti-diuretic effect of these compounds could cause
patient discomfort upon administration.
In order to analyze the overall effectiveness of each of the drugs in
treatment of UI, the raw data in Tables 1-5 has been subjected to
statistical analysis and compiled in Table 6. Data for each factor for
each drug administered are compiled on a weighted scale. For example, the
raw data for volume of first voiding has been scored on a scale of 1-7,
mean volume voided during observation has been scored likewise. The lower
a score received for a particular compound, the better the performance
exhibited by that compound with respect to that particular factor.
The scores for each factor are then added and the composite scores
obtained. The composite scores are then ranked in order of success, again,
lower numbers being preferred. These composite rankings are listed in the
last two columns of Table 6.
The composite rankings are presented in two columns, the first being a
composite rank for scores from volume of first voiding, mean volume,
diuretic effect and frequency. The second column also takes latency period
into effect. The composite ranks were compiled in this way due to the
difficulty in measuring latency term.
As can be seen from Table 6,
trimethylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl,1-cyclohexyl-1-phen
ylacetyl-thiol-S-(2-diethylaminoethyl)-ester.HCl,
palmitoyl-thio-S-(2-diethylaminoethyl)-ester.HCl,
phenylacetyl-thio-S-(2-diethylaminoethyl)-ester.HCl,
4-t-butyl-benzoyl-thiol-S-(2-diethylaminoethyl)-ester.HCl,
4-phenyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl and
2-ethyl-butyryl-thio-S-(2-diethylaminoethyl)-ester.HCl all exhibit low
composite ranks whether latency is considered or not. The unusual combined
qualities of these compounds rank them separate from the others and
demonstrate their positive universal effect in treatment of urinary
incontinence.
To the best of my knowledge, the compounds of this invention have not
before been suggested for use for the treatment of neuromuscular
incontinence much less for the five factors particularly reported in this
specification. The article of Buehler et al "Physiologically Active
Compounds . . . " of October 1962 discloses a compound No. 104 appearing
in Table 1, but the compound or its synthesis was indicated as something
to be desired and that yields were low. Although some of the compounds of
Buehler were tested for mydriatic activity and cerebral stimulation,
compound 104 was not subjected to tests. Indeed, Buehler attributed
activity to the presence of a hydroxyl group rather than a hydrogen group
on the alpha-carbon atom. Although I am the inventor of some patents which
include the 1-cyclohexyl-1-phenylacetyl-thiol-S-moiety, they do not have
the diethylamino moiety attached to the sulfur. For example, different
groups attached to the sulfur atom include the Davis Pat. Nos. 4,857,535
and 4,721,783, but neither suggests the remarkable effects obtained in
accordance with this invention. I am also the inventor named in U.S. Pat.
Nos. 4,707,480 and 4,432,977, which are directed to phenylacetyl moieties
attached to the alpha-carbon, as distinguished from phenylcyclohexyl
moieties.
It is accordingly highly unexpected, as reported in the specification, the
tests reported in the Tables and particularly in the composite scores
reported in Table 6, that highly surprising and highly beneficial results
were obtained from the particular pharmacological agents of this invention
in enhancing bladder capacity and reducing voiding frequency.
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